Synthesis and cytotoxic activity of pyranophenanthridine analogues of fagaronine and acronycine.
Condensation of 5-amino, 6-amino, 7-amino and 8-amino-2,2-dimethyl-2H-chromenes with either 6-bromoveratraldehyde or 6-chloropiperonal afforded the corresponding Schiff bases, which were subsequently reduced to the corresponding benzylchromenylamines 30-33 and 36-39. Lithium diisopropylamide-mediated cyclization of those amines, followed by spontaneous air oxidation, afforded pyranophenanthridines 3-14. The cytotoxicity of compounds 3-14 was evaluated against L1210 and HT29 cell lines. 9,9-Dimethyl-9H-pyrano[3,2-b]phenanthridines appear to be the most promising compounds of the series, since both the dimethoxy derivative 11 and the methylenedioxy derivative 12 exhibit significant cytotoxic activity. Compound 12 was the most active and induced a massive accumulation of cells in G2 + M phases, suggesting that the cytotoxicity is due to a perturbation of the integrity or function of DNA.
Razafimbelo
J
J
Laboratoire de Pharmacognosie de l'Université René Descartes, URA au CNRS No 1310, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Baudouin
G
G
Tillequin
F
F
Renard
P
P
Léonce
S
S
Pierré
A
A
Atassi
G
G
D000175:Acronine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D053119:Benzophenanthridines; D002453:Cell Cycle / Q000187:drug effects; D003500:Cyclization; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D010617:Phenanthridines; C002066:fagaronine; D000175:Acronine